Recipient Organization
TUFTS UNIVERSITY
200 WESTBORO ROAD
N. GRAFTON,MA 01536
Performing Department
BIOMEDICAL SCIENCES
Non Technical Summary
The current global population of the most deadly human malaria parasite, Plasmodium falciparum, is thought to have undergone a bottleneck sometime within the past several thousand years. Despite a recent common origin, P. falciparum populations are characterized by a high degree of genetic variation, which provides the great adaptive potential by which the parasite evades the host immune response. This work will increase our understanding of the genomic evolution of this parasite and will yield valuable information for intervening in disease transmission.
Animal Health Component
25%
Research Effort Categories
Basic
75%
Applied
25%
Developmental
(N/A)
Goals / Objectives
The current global population of the most deadly human malaria parasite, Plasmodium falciparum, is thought to have undergone a bottleneck sometime within the past several thousand years. Despite a recent common origin, P. falciparum populations are characterized by a high degree of protein polymorphism, particularly among certain immunodominant surface proteins. This extensive genetic variation provides the great adaptive potential by which the parasite evades the host immune response. The major objective of this proposal is to determine not only the degree of antigenic diversity in P. falciparum populations, but also to determine the principle mechanisms by which this variation is generated and maintained. This work will increase our understanding of the genomic evolution of this parasite and will yield valuable information for evaluating appropriate strategies for intervening in disease transmission.
Project Methods
We will examine the genetic polymorphism among natural isolates of P. falciparum from several endemic African sites. From these isolates, we will quantify the polymorphism among several molecular markers, which are dispersed on three completely sequenced chromosomes (chr2, chr3, and chr10). The genetic loci to be examined are three encoded surface protein genes--circumsporozoite protein (Csp, on Chr2) and merozoite surface protein-2 (Msp-2, on Chr3), and the 25kd P. falciparum sexual-stage antigen (pfs25, on Chr10). Each of these loci is life cycle-stage-specific in its expression and is the target of one or more vaccines currently in development. In addition to these protein-encoding genes, we will type several highly polymorphic microsatellite loci arrayed on the same three chromosomes. The resulting multi-locus genotype of each isolate will be used to test directly; (1) the level of meiotic recombination among genomes of natural P. falciparum isolates, (2) the
extent of diversifying selection among the crucial protein-encoding genes, (3) the role of slipped-strand (mitotic) mutation in maintaining variability in immunogenic, nucleotide-repeat loci (Csp and Msp-2).